Prostate cancer is the most commonly diagnosed malignant cancer in males in the United States and is the second leading cause of male cancer mortality. Surgery and/or radiation therapies can be employed to treat prostate cancer and further to prevent progression of the disease. However, in some cases systemic therapy based on inhibiting the androgen receptor (AR) is employed.
The androgen receptor is a steroid receptor transcription factor which promotes the growth and survival of both normal and cancerous prostate cells. Androgen ablation is used to block the activation or activity of androgens initially and often results in a favorable clinical response. However, prostate cancer can continue to progress and becomes resistant to androgen ablation, a disease status referred to as “castration-resistant prostate cancer.”
Clinical findings demonstrate that a majority of castration-resistant prostate cancers still express AR and androgen-dependent genes, indicating that the AR-signaling pathway is functional in the absence of androgens or in the presence of low levels of androgens (Chang, C. S. et al., Science 240, 324-6 (1988); Lubahn, D. B. et al., Mol Endocrinol 2, 1265-75 (1988)). Several independent studies have also shown that AR is essential for both hormone sensitive and recurrent hormone refractory prostate cancer (McPhaul, M. J. et al., J Investig Dermatol Symp Proc 8, 1-5 (2003); Heinlein, C. A. et al., Endocr Rev 25, 276-308 (2004)). Mutations and amplification of AR, alterations in protein kinases, growth factors and nuclear receptor coactivators have all been proposed to modulate AR signaling and may, therefore, play key roles in the development of androgen independence of prostate cancer (Feldman, B. et al., Nat Rev Cancer 1, 34-45 (2001); Lubahn, D. B. et al. Mol Endocrinol 2, 1265-75 (1988); Kuiper, G. G. et al., J Mol Endocrinol 2, R1-4 (1989)). Increased AR expression level has also been shown to associate with the development of resistance to anti-androgen therapy (McPhaul, M. J. et al., J Investig Dermatol Symp Proc 8, 1-5 (2003)).